IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells

Sureshbabu, A and Okajima, H and Yamanaka, D and Tonner, E and Shastri, S and Maycock, J and Szymanowska, M and Shand, J and Takahashi, S-I and Beattie, J and Allan, G J and Flint, David (2012) IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells. Journal of Cell Science, 125 (7). pp. 1693-1705.

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Abstract

Maintenance of tissue boundaries is crucial for control of metastasis. We describe a novel signalling pathway in which epithelial cell disruption can be minimised and thereby restricts epithelial-mesenchymal transgressions. This involves IGFBP-5 release from apoptotic cells, which increases epithelial cell adhesion on mesenchymal but not epithelial ECM and involves direct interaction of IGFBP-5 with α2β1 integrins. IGFBP-5 also induced adhesion to vitronectin in the absence of αVβ3 integrin, the vitronectin receptor, again via an α2β1 integrin-dependent action, suggesting that IGFBP-5 can induce spreading on matrices, even in the absence of the integrins normally used. Using IGFBP-5 mutants we demonstrate that the effect is IGF-independent but requires the heparin-binding domain in the c-terminus of IGFBP-5. A truncated c-terminal mutant of IGFBP-5 also induced adhesion. Adhesion induced by IGFBP-5 was cdc42-dependent and resulted in activation of ILK and Akt. Consistent with these changes, IGFBP-5 facilitated prolonged cell survival in nutrient-poor conditions and decreased phosphorylation of the stress-activated kinase p38MAPK. Whilst IGFBP-5 enhanced adhesion, it inhibited cell migration although this was not evident using the truncated c-terminal mutant, suggesting that effects of IGFBP-5 on adhesion and migration involve different mechanisms. These responses to IGFBP-5 would be anticipated to reduce metastatic potential.

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